Recent studies show that ghrelin antagonists acting on growth hormone secretagogue receptor (GHSR) robustly attenuate excessive alcohol self-administration and associated alcohol reward. Findings generated by US indicate that the ghrelin antagonist D-Lys3-GHRP-6 (DLys) strongly and preferentially decreases alcohol drinking in the mouse "drinking-in-the-dark" (DID) model of binge-like excessive alcohol consumption, and that this decrease is accompanied by selective suppression of c-Fos expression in the centrally-projecting Edinger-Westphal nucleus (EWcp). The EWcp is the main brain source of the neuropeptide urocortin 1 (Ucn1, a highly potent endogenous ligand of corticotropin releasing factor receptors) and has been shown to be highly sensitive to ethanol and be involved in regulation of alcohol intake. We hypothesize that ghrelin antagonists can be used to decrease alcohol intake across different animal models and that GHSR can serve as an important target for development of pharmacotherapy of excessive alcohol consumption. The goal of this proposal is to test this hypothesis and identify behavioral, anatomical and molecular mechanisms contributing to this decrease. This goal will be addressed in the three specific aims. In specific aim 1 we will test the ability of different doses of GHSR antagonists to decrease alcohol intake across different phases and different animal models of excessive alcohol consumption. In specific aim 2 we will investigate the anatomical substrates of ghrelin's effects on excessive alcohol drinking using knock-in GHSR null mutant mice and intracranial injections into specific brain regions. In specific aim 3 we will investigate the molecular mechanisms of ghrelin's involvement in regulation of excessive alcohol intake by analyzing levels of Ghsr mRNA after excessive alcohol intake in mice, rats and non-human primates and by testing whether signal transduction mechanisms induced by ethanol in EWcp are attenuated by administration of GHSR antagonists PUBLIC HEALTH RELEVANCE: Excessive alcohol use and alcoholism are major public health concerns, with alcohol causing approximately 4% of deaths globally. Our studies will provide a comprehensive basis for the potential of the use of ghrelin antagonism in the treatment of alcohol-use disorders and alcoholism.